Many pharmaceutically-active compounds that have therapeutic values to human beings are effective only in microgram quantities or in time-released quantities. There are, however, many problems inherent in the administering of these pharmaceutically-active compounds to human beings. For instance, if the pharmaceutically-active compound is to be administered by the use of a granular or powdered drink mix, it may be difficult to distribute the microgram quantities of the compound evenly. "Hot spots," where the compound is present in larger amounts, or "cold spots," where the compound may not be present at all, are conditions which make the administering of microgram quantities of a pharmaceutically-active compound difficult. This delivery problem is particularly associated with pharmaceutically-active compounds that are potent and must be delivered in fairly large or small quantities.
The distribution of pharmaceutically-active compounds is further hindered by the fact that these compounds are commonly delivered in time-released formulations. The time-released formulations used for the delivery of these compounds usually include a gel-forming dietary fiber. One type of gel-forming dietary fiber known in the art is guar gum. Guar gum (Cyamopsis Tetragonoloba), a galactomanan polysaccharide, and other gel-forming fibers such as psyllium hydrophilic mucilloid, have been recognized for some time to have a therapeutic value for lowering cholesterol and helping to regulate blood sugar.
Although guar gum is used in the food industry for various purposes as a food additive, it presents certain problems even at fairly low levels. Unfortunately, the gel-forming dietary fibers, such as guar gum, are known to incompletely dissolve by forming an impenetrable layer of gel around an undissolved fiber core when introduced into a liquid for dissolving the fibers. This impenetrable layer prevents the pharmaceutically-active compound within the gel-forming dietary fiber from being released from the tablet or granule in which it is contained. These problems are exacerbated even further when the gel-forming dietary fiber is used in granular or powdered drink mix formulations. The gel-forming dietary fiber is not only extremely difficult to mix and dissolve, but what small amount does hydrate immediately may form a thick gel which becomes impossible to drink.
Various additives normally used as disintegrants to break up tablets, such as crosslinking or wicking agents or microcrystalline cellulose, however, do not solve the problem of dispersing the gel-forming dietary fiber in a solution. It has been discovered, however, that the inclusion within the tablet or granule of a mineral salt that produces a physiologically-acceptable gas will safely and effectively disperse the gel-forming dietary fiber and will thus prevent the formation of an impenetrable gel around the tablet or granule. For instance, Day and Kuhrts (U.S. Pat. No. 4,824,672) teach the use of mineral carbonates to enhance dispersion of guar gum and other gummy fibers.
The use of a suspension agent with a gum to overcome some of the problems associated with using gums as stabilizers in the food industry have been described, however, the suspension agents form slurries which are not suitable for a pharmaceutical dosage form. For instance, Steinitz (U.S. Pat. No. 2,935,408) describes the use of a suspension agent with a gum. The gum is predispersed in a non-aqueous water-free liquid matrix, thereby to condition it for further dispersal throughout an aqueous carrier. One suspension agent used was glyceryl monosterate. A slurry was formed, which can be used as a stabilizer to be added to an aqueous solution such as a gravy, salad dressing, toppings, jams, etc. This slurry, however, is not suitable for a pharmaceutical dosage form.
Further, efforts to inhibit the viscosity of the gel-forming dietary fiber have proven futile for pharmaceutical purposes. For instance, Showa Sangyo (J.P. 59175436) discloses inhibiting the viscosity (gelation) of polysaccharides (e.g., guar gum, etc.), by treating the polysaccharides with high pressure or ultrasonic waves. However, this treatment could destroy the activity of the guar gum by producing a structural change, which would destroy the pharmaceutical benefits of the gel-forming dietary fibers.
Other efforts to form particles of gel-forming dietary fibers by agglomeration, although effective, have proven difficult to control. For instance, Heath (G.B. 2030583) discloses the formation of a granulate of guar by agglomeration. The agglomeration produces powder particles that will dissolve in water, producing drinkable mixtures. The granules of guar are then formed by spraying the powder with atomized water and then drying the granules to create particles of 100 to 1000 microns having a water content of 5 to 25% by weight. The problem with this process of forming guar particles is that it is very difficult to control particle growth when spraying guar with just water.
Further, the step of coating the gel-forming dietary fibers and pharmaceutically-active compound granules with a pre-swelled hydrocolloid has been described, however, these combinations suffer from the problem of incomplete dispersion or hydration. For instance, U.S. Pat. Nos. 4,790,991, 4,747,881, and 4,818,539 disclose coating dietary fibers and drugs with a pre-swelled hydrocolloid, wherein the substrate (drug or fiber) and the hydrocolloid are not the identical material, and wherein the substrate contains cholestyramine. The hydrocolloids are selected from the group consisting of natural and modified gums, cellulose, modified celluloses, pectin, mucilages, modified starches, etc. U.S. Pat. Nos. 4,747,881, in particular, discloses coating locust bean gum with carboxy methylcellulose. The particles created tend to form small spheres which have a gel coating around their circumference when they are hydrated. They hydrocolloid coating slows down the gelation of the aggregate, but each individual particle does not fully disperse or hydrate when the hydrocolloid layer dissolves and the gastric fluid comes in contact with the core material (substrate).
Others have tried using gelatin hydrolysates to inhibit the gelation of gel-forming fibers, however, this process is not useful for administering therapeutic amounts of the gel-forming dietary fiber. For instance, EPO 0007619 discloses the use of gelatin hydrolysates to inhibit the gelation of polysaccharide gums such as guar or locust bean gums. The gelation of the gum is inhibited by admixing or blending it with gelatin and adding an effective quantity of alkalinizer such as sodium glycinate. The preferred ratio of guar gum to gelatin, however, is 0.5:1, which means that there is twice as much inhibitor as guar gum. This severely limits the usefulness of that mixture, since the guar gum must be taken in large amounts to be therapeutically effective, and one would be consuming large amounts of gelatin with it. Thus, in a daily dose of 15 grams of guar gum, one would also be consuming 30 grams or more of gelatin, which is undesirable.
Others have attempted to coat the gel-forming dietary fiber with a layer of protein, however, this process produces a composition which gels slowly when mixed with water. For instance, GB 2021948 discloses the coating of gums such as guar gum or locust bean gum with a layer of protein such as soya flour, gluten, or casein having a greater tendency to absorb water than the gum. The gum and the coating substance are mixed in preferably equal amounts with water to produce a dough which is dried and crushed. The resulting composition gels slowly when mixed with water.
Accordingly, it is an object of the present invention to provide a granular drug delivery system that delivers an effective dose of a pharmaceutically-active compound when dispersed in an orally-digestible liquid.
It is a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid where the gel-forming dietary fiber will mix and dissolve and will not hydrate immediately to form a thick gel which is impossible to drink.
It is yet a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid, the composition including a mineral salt that releases a physiologically-acceptable gas when ingested to mechanically disperse the gel-forming dietary fiber.
It is yet a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid, the composition including a fiber, protein or starch coating on the granules to further facilitate the dispersion of the gel-forming dietary fiber and the dispersion of the pharmaceutically-active compound.
It is yet a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid and that delivers an effective dose of a pharmaceutically-active compound without the formation of "hot spots" or "cold spots" of the pharmaceutically-active compound.
It is yet a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid and that delivers an effective dose of a pharmaceutically-active compound where the pharmaceutically-active compound is provided in microgram quantities.
It is yet a further object of the present invention to provide a granular drug delivery system including a gel-forming dietary fiber that can be readily made into an orally-ingestible dispersion by admixture with a liquid and that delivers an effective dose of a pharmaceutically-active compound where the pharmaceutically-active compound is chromium, niacin, aspirin, ibuprofen, an analgesic, an antihypercholesteromeric, a vitamin, a stimulant, an appetite suppressant, an antibiotic, an antihistamine, phenylpropanolamine hydrochloride, caffeine, a decongestant, an antitussive, or a mineral supplement.
It will be appreciated from the foregoing that there is a definite need for a granular drug delivery system that provides the above objects. The present invention fulfills these needs.